Trisulfureted heterocyclic compounds



Patented Sept. 7, 1954 TRISULFURETED HETEROCYCLIC COMPOUNDS OlivierGaudin, N euilly-sur-Seine, .France No Drawing. Application May 4, 1951,Serial No. 224,671

1 Claim. 1

This invention relates to a new class of organic trisulfureted compoundsand to processes for preparing such compounds. Certain of thesecompounds are particularly useful for therapeutic purposes.

This is a continuation-in-part of my application Ser. No. 763,167, filedJuly '23, 1947, now Patent No. 2,556,963.

The class of compositions which may undergo the trisufurization reactionof the present invention comprises mono and disubstituted propenes ofthe general formula 'RiRz'wsl-lr) wherein R1 and R2 are any radicalswhich will remain stable under the conditions of the sulfurizationreaction, such as hydrogen, or aryl or alkyl radicals, provided they arestable in the presence of sulfur at a temperature up to 250; examples ofsuch radicals are methyl, phenyl, naphtliyl.

It is possible also that the aforementioned alkyl or aryl radicals mayinclude functional groups, provided that these groups are stable underthe conditions of the sulfurization reaction. Phenol functions andphenol ether functions may, for instance, be introduced in the R1 or R2radical.

The invention comprises also processes of manufacturing such newcompositions of matter.

It is well known that rather unstable additive compounds of sulfur areobtained by the action of sulfur on unsaturated organic compounds, suchas for instance terpenes. However, the oily or tar-like substances thusobtained are not well defined chemical compounds; they are polymers witha very variable sulfur content from which no crystallized product hasever been obtained.

In the prior art, a large number of processes have been disclosedconcerning action of sulfur on organic compounds: for instance, animmensely important technical process is the vulcanization of rubber byaction of sulfur on crude rubber.

In this sort of sulfurization it is generally thought that the sulfuratoms add on unsaturated esters, such as double bonds.

In the process contemplated in this invention, the propenylidene (C'sH4)group undergoes a substitution reaction, the hydrogen atoms beingreplaced by sulfur according to the following formula:

This reaction,from the chemical point of view, was completelyunexpected, and. nothing in the prior art gave the least clue that suchreaction were possible.

In fact this reaction is remarkable :in more than one respect:

(a) A three carbon chain is necessary. This contrasts with thesulfurization processes :described in the prior art which related toparticular carbon atoms in a molecule, or to double bonds whichconstitute a two carbon chain. Such actions on two carbon chains aredisclosed, for instance, .Biittchers application, A. vP. C. Ser. No.415E982, published April 220., .1943.

(b) Four hydrogen atoms :are simultaneously replaced .by three sulfuratoms.

It is quite unexpected that four hydrogen atoms must disappearsimultaneously in a substitution reaction. In the general chemicalknowledge it is well known that the ordinary course of substitutionreactions is stepwise, one hydrogen being replaced after the other, andthe con'e'sponding steps being easily ascertained.

It is furthermore unexpected that four hydrogen atoms are replaced bythree sulfur atoms, as sulfur at least divalent and thus it is expectedthat four hydrogens must be replaced by two sulfur atoms at the most.

The invention is further distinguished from the prior art in that itcomprises .new compositions of matter of the general character set forthabove, from which it is possible to :derive pure and stable chemicalcompounds, some of which have been found to be of considerabletherapeutic value. Such new compositions of matter can be obtainedchemically pure in their crystallized form. Their molecule contains 3atoms :of sulfur.

The expianation of these unexpected facts has been found in my work, bywhich the structural formulae of the new trisuifureted products havebeen established. According to these results the trisulfurizationreaction proceeds according to the following generai formula:

R2 R1 1 I or alternatively:

According to the last formula, the trisulfureted compound must be nameddithiole-1-2-thiones-3. whose parent compound is:

11 5 rid o= s In the preceding general formula, the radicals R1 and R2may be, for example, hydrogen atoms, alkyl, aryl, hydroxyaryl (phenol)or alkoxyaryl (phenol ether) radicals.

One of the new compositions of matter of the present invention whichwill be described more in detail below, results from the action ofsulfur on anethol or on its isomer estragole, wherein R1 is an anisyl(Cl-I3OCal-I4) and R2 is an hydrogen atom. A crystallized substance hasbeen isolated from this composition: Trithioparamethoxyphenylpropene. Ihave described this new composition of matter in Comptes Rendus of thevAcademy of Sciences of Paris, vol. 224, pages 479-481 and pages577-578. The physiological and therapeutic properties of this newcomposition of matter were described by me in Comptes Rendus of theAcademy of Medicine of Paris, vol. 131, pages 265-269.

Trithioparamethoxyphenylpropene has an extremely small toxicity. Itrequires a dose of 6 grams per kilogram of animal to cause the death ofa guinea pig in 36 hours. That is over 9,000 times the normal humantherapeutic dose. It may therefore be considered practically nontoxic.

The most important physiological properties of the new composition ofmatter reside in its very considerable choleretic action and in adiuretic action provoking the elimination of excess urea.

As a human therapeutic, this new composition of matter may, forinstance, be administered in an average dose of 0.0125 gram for a totaldosage of 0.0375 to 0.075 gram in a period of 24 hours. It may be takenin the form of pellets or pills or in any other form that can beadministered through the mouth.

I have investigated 150 clinical cases and treated them withtrithioparamethoxyphenylproprene, and I have obtained very satisfactoryresults, particularly in the case of hepatic disorder, gall bladderdisorders, and allergies or dermatoses of hepatic origin.

My investigations have led to the following broad conclusions:

1. Trithioparamethoxyphenylpropene has a constant choleretic action;

2. In the case of every syndrome wherein there exists a functionaltrouble of the biliary secretion, the clinical improvement resultingfrom doses of 0.0375 to 0.075 gram per 24 hours is marked.

3. The most constant results are obtained in cholocystitis with orwithout associated manifestations.

In the manufacture of the new class of compositions of matter of thepresent invention, use may be made of elementary sulfur in any one ofits varieties as well as of substances easily liberating sulfur, such aspolysulfides or halogen sulfides, for instance.

As organic substances, use may be made of various compounds of vegetalorigin such as estragole, eugenol, safrole, amongst the allyl compounds;anethol, iso-eugenole, iso-safrole, amongst the propenyl compounds.

. It is also possible to employ natural oils containing any of theabove-mentioned substances such as anise oil for anethol; alternatively,it is also practicable to use synthetic products of the general type setforth above, for instance allylphenols prepared according to the wellknown Claisen process.

The process according to the present invention may be carried out in thepresence of suitable catalysts, such as vulcanization catalysts. It isalso possible to operate in the presence of solvents.

The reaction is achieved by heating the reacting substances in an openreceptacle up to temperatures varying according to the reactingsubstances chosen.

Example I There is heated in an open receptacle a mixture of:

The reaction starts at about 148 C. and the temperature is raised above200 C. A considerable liberation of hydrogen sulfide is observed. Duringthe reaction, the mass becomes progressively thicker and thicker. Aftercooling, the mass is first treated with a solvent, such as boilingacetone, then filtered, and is allowed to crystallize.

After several fractionized crystallizations during which other solventsmay be added, there is finally obtained a crystallized substance inredbrown needles having no smell but a bitter taste and melting at108-109 C. This substance is insoluble in water and slightly soluble inmost of the organic solvents. Further, the new composition of matter isperfectly stable and does not oxidise in the air.

The reaction may be represented by the following formula:

In the process of Example I, anethol is replaced by estragole. Theresulting substance has in every respect the same aspect as thesubstance resulting from the process described in the preceding example.It melts also at 108-109 C. either in pure state or mixed with thesubstance resulting from the anethol treatment.

The reaction may be represented by the following formula:

In the foregoing processes, there is employed a quantity of sulfurcorresponding to atoms of sulfur per mol of organic substance.

There is no use in substantially increasing the proportions of sulfursince the surplus amount of sulfur does not react in the process in viewof secondary reactions, and the surplus quantity of sulfur thusintroduced would be found unaltered at the end of the reaction.

The amount of sulfur may thus be limited since it does not totally reactbut it is not desirable to reduce the quantity of sulfur below a certainproportion, since this would tend to reduce the yield of the reaction.

It is not desirable to work the reaction below 200 C. in the open air,since too low a temperature would slow down the reaction, thusincreasing the duration of the heating period. The heat should not beapplied too briskly since the gases produced might lead to an explosion.Further, too brisk a heating process lowers the efficiency of thereaction through the production of tar-like substances.

Some other examples of trisulfurization reactions in accordance with theinvention as stated above and following the process steps disclosed inExample I are:

. CH2CH=CH2 OHIO S-S H2O What is claimed is: As a new composition ofmatter, a trisulfureted compound having the formula:

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 2,535,705 Stevens et a1. Dec. 26, 1950 2,556,963 Gaudin June'12, 1951

